High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer

Xiaoyong Fu; Resel Pereira; Chia-Chia Liu; Carmine De Angelis; Martin J Shea; Sarmistha Nanda; Lanfang Qin; Tamika Mitchell; Maria L Cataldo; Jamunarani Veeraraghavan; Vidyalakshmi Sethunath; Mario Giuliano; Carolina Gutierrez; Balázs Győrffy; Meghana V Trivedi; Ofir Cohen; Nikhil Wagle; Agostina Nardone; Rinath Jeselsohn; Mothaffar F Rimawi; C Kent Osborne; Rachel Schiff

doi:10.1016/j.celrep.2023.112821

High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer

Cell Rep. 2023 Aug 29;42(8):112821. doi: 10.1016/j.celrep.2023.112821. Epub 2023 Jul 18.

Authors

Xiaoyong Fu¹, Resel Pereira², Chia-Chia Liu³, Carmine De Angelis⁴, Martin J Shea³, Sarmistha Nanda³, Lanfang Qin³, Tamika Mitchell³, Maria L Cataldo⁴, Jamunarani Veeraraghavan³, Vidyalakshmi Sethunath³, Mario Giuliano⁵, Carolina Gutierrez⁶, Balázs Győrffy⁷, Meghana V Trivedi⁸, Ofir Cohen⁹, Nikhil Wagle¹⁰, Agostina Nardone¹¹, Rinath Jeselsohn¹¹, Mothaffar F Rimawi³, C Kent Osborne¹², Rachel Schiff¹³

Affiliations

¹ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: xiaoyonf@wecurecancer.org.
² Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
³ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
⁵ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
⁶ Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Department of Bioinformatics, Semmelweis University, 1085 Budapest, Hungary; RCNS Cancer Biomarker Research Group, Institute of Enzymology, Magyar Tudósok körútja 2, 1117 Budapest, Hungary.
⁸ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pharmacy Practice and Translational Research, University of Houston, Houston, TX 77204, USA; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva 84105, Israel.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA.
¹² Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
¹³ Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: rschiff@bcm.edu.

PMID: 37467106
DOI: 10.1016/j.celrep.2023.112821

Abstract

Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.

Keywords: CP: Cancer; breast cancer; cistrome; endocrine resistance; enhancer; epigenetic; estrogen receptor; forkhead box protein A1; metastasis; secretome; transcription factor.